A dramatic shift has occurred over the last decade in the route of administration of certain drugs of abuse in the United States. For example, the intravenous route for heroin has historically been the favored method of drug administration. This is changing with increased reports of intranasal and smoked administration of heroin. The reasons for these changes may include social and environmental factors such as the ease and convenience of smoking, avoidance of needle-transmitted diseases, and possible pharmacologic differences produced by the different routes of administration. In contrast to cocaine, tobacco (nicotine) and cannabis (tetrahydrocannabinol) have almost always been administered via smoking in the United States. The route of drug administration is a determinant of the toxicity and addictiveness of a given drug. The smoked route results in significant morbidity and mortality. Studies examine the influences exerted by routes of administration (intranasal, intravenous, and smoked) on pharmacokinetic parameters and drug-induced behavioral and physiologic effects of cocaine, methamphetamine, cannabis, heroin and nicotine. Physiological and behavioral measures are collected before and periodically after drug administration. Concurrent blood specimens are collected and analyzed by gas chromatography/mass spectrometry and liquid chromatography/mass spectrometry for drugs and metabolites. Behavioral measures of subjective effects and cognitive and psychomotor performance are evaluated by the different routes to compare magnitude of responses including measures of abuse liability. Investigation of plasma concentrations following administration of drugs by alternative routes permits determination of drug bioavailability, an important factor in route selection. Physiologic responses vary according to the speed, magnitude and duration of drug concentrations at the site of action. Intranasal administration was characterized by lower plasma concentrations and a slower onset of pharmacologic effects that were generally of lower magnitude than those observed by other routes of administration. These findings suggest that smoked cocaine (crack) has a higher abuse liability and greater dependence-producing properties than equivalent doses of cocaine administered by the intravenous or intranasal route. Other studies found that liking scores were similar for smoked doses of heroin, cocaine, and nicotine. Together, these studies indicate that the smoked route of drug administration is associated with high levels of abuse liability and that a drug's abuse potential is not an inherent property of the drug, but can vary depending on how the drug is delivered.